Method to determine the risk for side effects of an SSRI treatment in a person

ABSTRACT

A new method is found to determine an increased risk for side effects of an SSRI treatment in a person by genotyping the person for the presence of the 102 C/C DNA sequence in the 5-HT 2A  receptor gene. This provides for a method to improve the treatment of an SSRI responsive disorder and in particular depression.

FIELD OF THE INVENTION

[0001] The invention relates to a method to determine the risk for sideeffects of an SSRI treatment in a person and to a method to improvemedical treatment of a disorder, which is responsive to treatment with aselective serotonin reuptake inhibitor (SSRI).

BACKGROUND OF THE INVENTION

[0002] SSRI's are widely used for the treatment of various disorders.Major depression is the most common among those disorders treated withan SSRI. Other well-known disorders that can be treated with SSRI's aredysthymia, premenstrual dysphoric disorder, panic disorder, obsessivecompulsive disorder, social phobia, post-traumatic stress disorder,generalised anxiety disorder, obesity and alcoholism (Schatzberg J. ClinPsychiatry, 61, Suppl 11: 9-17, 2000; Masand and Gupta, Harvard RevPsychiatry, 7: 69-84, 1999). Evidence is accumulating that such drugshave also beneficial effects in less common disorders, such astrichotillomania, paraphilia and related disorders and borderlinepersonality disorder. Benefits are also obtained with use of an SSRI insmoking cessation and in the control of addictive behavior.

[0003] It occurs regularly that a once started treatment with an SSRIfails to have clear therapeutic results or has to be discontinued due topoor tolerance of side effects. Known side effects of SSRI's areheadache, nausea, appetite inhibition, agitation, sleep disturbance, anddisturbance of sexual functions, such as anorgasmia and loss of libido.In practice the overall therapeutic result of a regularly applied SSRItreatment is the resultant of the improvement of the disorder and theburden of negative side effects. In view of the existence ofalternatives to SSRI's for the treatment of disorders, treatment resultscan be improved when patients are selected for tolerance and chance ofsuccess of an SSRI. Patients at risk for negative side effects can betreated with a treatment other than a treatment with an SSRI.Consequently, it will be very useful if it were possible to predict theoccurrence of cumbersome side effects of a treatment with an SSRI.

[0004] It is a known assumption that the genetic make-up of a person cancontribute to the individually different responses of persons to amedicine (Roses, Nature 405:857-865, 2000). Examples of genetic factors,which determine drug tolerance, are drug allergies and severely reducedmetabolism due to genetic absence of suitable enzymes. A case of alethal lack of metabolism due to cytochrome P-450 2D6 genetic deficiencyis reported by Sallee et al J Child & Adolesc. Psychopharmacol, 10:27-34, 2000. The metabolic enzymes in the liver occur in polymorphicvariants, causing some persons to metabolise certain drugs slowly andmaking them at risk for side effects due to excessively high plasma druglevels. Many genes that are expressed in the brain such asneurotransmitter receptors and transporter proteins have polymorphicvariants. These variants may influence the interaction of a drug withcells of the brain, which may influence the frequency of drug sideeffects (Cravchik and Goldman, Arch Gen Psychiatry 57:1105-1114, 2000).Variants of the gene for the serotonin 2A receptor (5-HT_(2A) receptor)exist, which differ in one nucleotide at location 102. Alleles with 102Cand 102T exist. This particular polymorphism has been explored inattempts to find genetic predictors for schizophrenia symptomatology,suicidal ideation, alcohol dependency, bipolar affective disorder,fibromyalgia, Tourette's syndrome, and other diseases. Such attemptshave met with little confirmed success thus far (Bondy et al., Am J MedGenetics, 96:831-835, 2000; Massat et al., Am J Med Genetics,96:136-140, 2000; Serretti et al., Am J Med Genetics, 96: 84-87, 2000;Bondy et al., Neurobiol Diseases, 6:433-439, 1999; Du et al., Am J MedGenetics, 96:56-60, 2000).

SUMMARY OF THE INVENTION

[0005] Unexpectedly, it has now been found that it is possible todetermine an increased risk for side effects of an SSRI treatment in aperson by genotyping the person for the presence of the 102 C/C DNAsequence in the 5-HT_(2A) receptor gene.

[0006] This finding also enables that an improved treatment result for adisorder which is responsive to treatment with an SSRI, can be obtainedby genotyping the patients for the presence or absence of said DNAsequence and selecting a therapy which diminishes the risk for sideeffects of an SSRI treatment.

[0007] In particular, the improvement is obtained in the treatment ofdepression for which it is preferred to select as therapy administeringmirtazapine in an amount effective to treat depression in the personhaving the 102 C/C DNA sequence in the 5-HT_(2A) receptor gene.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0008] Genotyping a person for the presence of the 102 C/C DNA sequencein the 5-HT_(2A) receptor gene means screening patients to determine thetype and number of 5-HT_(2A) receptor alleles present in the patient.Such screening may be carried out by nucleic acid sequencing of DNA. Forexample, the screening may be accomplished by restriction isotypingmethods, which include the general steps of polymerase chain reactionamplification, restriction digestion, and gel electrophoresis. Screeningmay also be carried out by other types of nucleic acid sequencing, e.g.,by hybridisation or oligotyping, or by direct sequencing of DNAnucleotides.

[0009] 5-HT_(2A) receptor gene means the gene (designated as HTR2A)which encodes for the serotonin 5-HT_(2A) receptor. The 5-HT_(2A)receptor gene is located on chromosome 13q14-21. At location 102 a C->Tpolymorphism is known with about 40% frequency of the 102T allele in anormal Caucasian population. The terms allele and gene are usedinterchangeably herein. The DNA and amino acid sequences of the5-HT_(2A) receptor gene and the 5-HT_(2A) receptor itself are known andare available, e.g., at NCBI nucleotide accession No. NM_(—)000621 andprotein accession No. NP_(—)000612.

[0010] The term 102 C/C DNA sequence refers to homozygous presence ofcytidine at location 102 in both alleles for the 5-HT_(2A)-receptor. Theterms 102 T/C and 102 T/T refer to the heterozygous state, and thehomozygous state for thymidine at location 102 of the5-HT_(2A)-receptor, respectively. The homozygous C/C genotype occurswith a frequency of about 33% in Caucasian populations (Frisch, MolPsychiatry 4:389-392, 1999).

[0011] Side effects of an SSRI treatment are those related to SSRItreatment based on a positive correlation between frequency or intensityof occurrence and SSRI drug treatment. Such information is usuallycollected in the course of studies on efficacy of a drug treatment andmany methods are available to obtain such data. Resulting information iswidely distributed among the medical profession and patients receivingtreatment. Specifically identified SSRI treatment related side effectsare headache, dizziness, agitation, trouble concentrating,gastrointestinal disturbances, nausea, vomiting, diarrhea, appetiteinhibition, sleep disturbance, somnolence, insomnia and disturbance ofsexual functions, such as anorgasmia and loss of libido. Prematuredrug-related discontinuation of an SSRI treatment and drug-relatedadverse events are also included here within the definition of sideeffects of an SSRI treatment.

[0012] A treatment result is defined here from the point of view of thetreating doctor, who judges the efficacy of a treatment as a groupresult. Within the group, individual patients can recover completely andsome may even worsen, due to statistical variations in the course of thedisease and the patient population. Some patients may discontinuetreatment due to side effects, in which case no improvement in theircondition due to SSRI treatment can occur. An improved treatment resultis an overall improvement assessed over the whole group. Improvement canbe solely due to an overall reduction in frequency or intensity of sideeffects. It is also possible that doses can be increased or the dosingregime can be stepped up faster thanks to less troublesome side effectsin the group and consequently an earlier onset of recovery or betterremission of the disease.

[0013] A disorder, which is responsive to treatment with an SSRI, isdefined to be a disorder, which is, according to recommendations inprofessional literature and drug formularies, known to respond with atleast partial remission of the symptoms to a treatment with an SSRI. Inmost countries such recommendations are subject to governmentalregulations, allowing and restricting the mention of medical indicationsin package inserts. Other sources are drug formularies of healthmanagement organisations. Before approval by governmental agenciescertain recommendations can also be recognised by publications ofconfirmed treatment results in peer reviewed medical journals. Suchcollective body of information defines what is understood here to be adisorder which is responsive to treatment with an SSRI. Being responsiveto SSRI treatment does not exclude that the disorder in an individualpatient can resist treatment with an SSRI, as long as a substantialportion of persons having the disorder respond with improvement to theSSRI treatment.

[0014] In the section describing the background of the inventionexamples of SSRI responsive disorders were listed. Known disorders whichare responsive to treatment with an SSRI are, for example, majordepressive disorder, dysthymia, premenstrual dysphoric disorder, panicdisorder, obsessive compulsive disorder, social phobia, post-traumaticstress disorder, generalised anxiety disorder, obesity, bulimia nervosa,alcoholism, trichotillomania, paraphilia and related disorders,borderline personality disorder, smoking cessation and drug abuse.

[0015] The technical field defines an SSRI as a drug which inhibits thereuptake of serotonin in nerve terminals in the brain more effectivelythan the reuptake of noradrenaline and dopamine. Such drugs are treatedas a group with common properties due to this mechanism of action andthis selectivity. Known drugs specifically named as SSRI are fluoxetine,fluvoxamine, citalopram, cericlamine, femoxetine, sertraline,paroxetine, ifoxetine, cyanodothiepin and litoxetine, of whichfluoxetine, fluvoxamine, citalopram, sertraline and paroxetine are theones with which most experience is obtained and which are preferredindicators for defining the SSRI responsive disorders for which themethod according to this invention can be applied (Hermann, Canadian JClin Pharmacol 7: 91-95, 2000; Modell et al., Clin Pharm & Ther 61:476-487, 1997; Lucki et al., Neurosci biobehav. Rev 18: 85-95, 1994).

[0016] The method to obtain an improved treatment result comprises:

[0017] a) Diagnosing a person for having a disorder, which responds totreatment with an SSRI.

[0018] b) Genotyping the person to determine whether the person is ahomozygous carrier of 102C alleles of the gene for the5-HT_(2A)-receptor.

[0019] c) Adapt the further treatment of the person differentiallydepending on the presence or absence of the said sequence in the person.

[0020] This method does not necessarily prescribe these steps in theindicated sequence. In practice an SSRI treatment can be started beforethe steps to confirm the suitability of the treatment can be started.The genotyping serves to decide on timely adapting the further treatmentwhen the person is found to fall into the genotype category homozygous102 C/C for the 5-HT_(2A) receptor.

[0021] For further treatment the category (A) of persons of thehomozygous 102 C/C genotype is to be differentiated from the category(B) of persons of the 102 T/C and T/T genotypes.

[0022] Adapting the further treatment of the person differentiallydepending on the presence or absence of the said sequence in the personis a measure which should consist of the following measures: Forcategory A the further treatment should be either

[0023] 1) administering a below average dose of an SSRI, or

[0024] 2) co-administering a drug treatment which diminishes SSRI sideeffects, or

[0025] 3) instructing and helping the person to accept theinconveniences of the side effects, or

[0026] 4) starting or switching to an alternative, non-SSRI treatment.

[0027] For category B the further treatment should be either

[0028] 1) starting or continuing as if no information on said genotypeis available

[0029] 2) a more aggressive approach in the treatment with an SSRI, inthe case that an SSRI-treatment is or is to be selected, byadministering the person a higher dose or stepping up the dose in a moreprogressive regime than would be done if no information on the genotypewas known.

[0030] The adaptation for category A persons amounts to selecting atherapy diminishing the risk for side effects of an SSRI treatment forthe person. Preferred is to apply a therapy which is recognised to be analternative for a treatment with an SSRI.

[0031] When the genotyping is performed, or the result is known, afterstart of an SSRI treatment and the treated person is found to have the102 C/C genotype and side effects are experienced with SSRI treatment,then, because there is a high probability that the person willeventually discontinue SSRI treatment, the person's burden can bedecreased by applying an alternative treatment. As a result the timerequired to achieve an improvement can be reduced by applying analternative therapy, since the probability of eventually discontinuingtreatment with the SSRI is high in a person with the 102 C/C genotype.

[0032] The selection of a therapy which is recognised to be analternative for a treatment with an SSRI is defined by reference to thegeneral knowledge in this medical field. It is standard practise todiagnose a disorder in a person and select a therapy which is indicatedfor the disorder. An example of a reference manual for diagnosticmethods is the Diagnostic and Statistical Manual of Mental Disorders 4thedition (DSM-IV) published by the American Psychiatric Association,Washington, D.C. (1994). Supplementary to this the SSRI responsivedisorders can be identified objectively on the basis of recommendationsin government approved labels, by health management organisations and inconfirmed reports of positive treatment results in peer reviewed medicalliterature, it is similarly known to the skilled person that alternativenon-SSRI treatments are available. Examples of non-SSRI anti-depressanttreatments are, for example, treatments with drugs, which act byblocking the reuptake of norepinephrine, or by blocking α2 adrenergic orserotonin receptors. Specific alternative antidepressants arevenlafaxine, mirtazapine, nefazodone, doxepine and imipramine, of whichmirtazapine, of course in an amount effective to treat depression, ispreferred for the indication of major depression. Alternative treatmentsfor prescribing an SSRI can also be non-drug treatments, such asbehavioural therapies or electroconvulsive shock treatment.Benzodiazepine-like anxiolytic compounds can be used for anxietydisorders. A therapy diminishing the risk for side effects of an SSRItreatment can also be a treatment with a below average dose of the SSRIor providing an additional treatment to prevent side effects.

[0033] The amount of mirtazapine effective to treat depression will, ofcourse, vary and is ultimately at the discretion of the medicalpractitioner. The factors to be considered include the route ofadministration and nature of the formulation, the body weight, age, andgeneral state of health, and severity of the depression. Unlessotherwise stated, all weights of active ingredients referred to hereinare calculated in terms of the active drug per se. In general, asuitable dose of mirtazapine for administration to a human will be inthe range of 5 to 100 mg per day. In one embodiment, the suitable dosagerange for administration of mirtazapine to a human may be 15 to 45 mgper day. The desired dose may be presented as two, three, four, five, ormore sub-doses administered at appropriate intervals throughout the day.These sub-doses may be administered in unit dosage forms, for example,containing 15 mg, 30mg, or 45 mg, or any unit dosage useful to allowmultiple dosing in a single day.

[0034] No clear explanation of the effect of the invented method can begiven. It may be relevant that the 5-HT_(2A) receptor is located on themembrane of postsynaptic neurones and interacts with serotonin moleculesin the synaptic cleft. It has been theorised that the side effects ofselective serotonin reuptake inhibitors such as paroxetine are mediatedthrough this receptor. Genetic variants of the 5-HT_(2A) receptor mayalter the binding of serotonin to the receptor, or alter the signal thatthe activated receptor transmits to the postsynaptic neuron in thebrain. 5-HT_(2A) receptors are also located on smooth muscle cells inthe gastrointestinal tract and blood vessels. Carriers of the C/Cgenotype may have side effects such as gastrointestinal upset anddizziness after paroxetine due to altered reaction of smooth musclecells to serotonin stimulation of 5-HT_(2A) receptors. 5-HT_(2A)receptors are also thought to be important in level of alertness andsleep. Insomnia and agitation experienced by subjects carrying the C/Cgenotype may have been due to altered function of 5-HT_(2A) receptorsregulating alertness and sleep.

[0035] The 5-HT_(2A) receptor 102 T/C polymorphism is a “silent” geneticmarker that does not result in an amino acid substitution in thefunctional protein. Without implying any restriction on the claims anduse of the invention it can be suggested that the effect we have foundon intolerance to an SSRI of 102C/C genotype patients can be due toanother nearby variant in the gene that directly affects its function.The 102 T/C polymorphism and the functional variant are said to be in“linkage disequilibrium”, meaning that the 102 T/C variant is a markerfor a polymorphism in close proximity that affects the receptorfunction. However, this in no way diminishes the importance of the 102T/C polymorphism as a predictor of side effects to an SSRI, as found inthe present invention. Many existing medical tests are useful markersfor an underlying biological process. For example, the erythrocytesedimentation rate (ESR) is a commonly used marker for an inflammatoryreaction, even though it does not define the exact nature of theunderlying inflammatory disease.

[0036] To screen patients for the gene, genomic DNA can be extractedfrom EDTA-treated whole blood using, for example, the Puregene DNAextraction kit (available from Gentra Systems). Genotypes can bedetermined using restriction isotyping (restriction enzyme isoformgenotyping) following in general the method of Du et al. (Am J MedGenet. 2000 Feb 7;96(1):56-60). Thus, the 5-HT2A gene presence in theextract can be amplified by about 30 cycles of polymerase chain reactionprimed by the primers 5-HT2AR-1 (agcagaaactataacctgtt) and 5-HT2AR-2(caagtgacatcaggaaatag) followed by a final extension step. This PCRproduct can be digested with a specific restriction enzyme cutting5-HT2A polynucleotides as a consequence of recognition of the 102 C/Tdifference such that one allele remains undigested, yielding the full410 base pair fragment, while the other allele is cut into twofragments. The digested samples can then be separated and determined bygel electrophoresis.

EXAMPLE

[0037] Treatment Protocol

[0038] 122 patients with major depression were treated for 8 weeks withparoxetine. All subjects were 65 years of age or older and had been freeof major medical problems for at least 3 months. At screening, all metDSM-IV criteria for major depression (single or recurrent), had MiniMental State Examination scores above the 25th percentile for their age,and had a Hamilton Depression Rating Scale 17-item (HDRS-17) score of atleast 18. Patients were excluded for clinically significant-laboratoryabnormalities, drug or alcohol abuse, psychosis, recent suicide attempt,and psychiatric conditions other than major depression, or treatmentwith antidepressant medications within 7 days of commencing the study.

[0039] Initial treatment was with 20 mg of paroxetine (two 10 mgcapsules) given each evening. On day 14, doses were increased to 30 mgof paroxetine once daily. At days 28 and 42, dose increases to 40 mg ofparoxetine were allowed if the patient had a Clinical Global Impression(CGI) improvement score of greater than 2. Patients were seen in clinicat days 7, 14, 21, 28, 42, and 56 of treatment.

[0040] Genetic Analysis

[0041] Genomic DNA was extracted from EDTA-treated whole blood using thePuregene DNA extraction kit (Gentra Systems). Genotype for the 102 T/CDNA sequence polymorphism in the 5-HT_(2A) receptor gene was determinedusing the method of Du et al. (Am J Med Genet. 2000 Feb 7;96(1):56-60).Specifically, 2.5 μL 10X PCR buffer (Applied Biosystems); 0.25 μL of 10mmol/L dNTP (Amersham); 0.05 μL of primer 5-HT2AR-1(agcagaaactataacctgtt) at 100 pmol/μL; 0.05 μL of primer 5-HT2AR-2(caagtgacatcaggaaatag) at 100 pmol/μL; and 0.1 μL of Taq polymerase at 5U/μL (Applied Biosystems) are mixed with 1 μL of genomic DNA at 0.23 to1.1 μg/μL in a total volume of 25 μL. After an initial 5 minutedenaturing step at 95° C., the reaction mixture goes through 30 cyclesof polymerase chain reaction (PCR) (95° C. for 1 min, 52° C. for 30 sec,and 72° C. for 1 min), followed by final extension at 72° C. for 10minutes. 8 μL of this PCR product is digested with 0.5 μL of the Msp Irestriction enzyme (20 U/μL, NEB), 1.5 μL of 10X buffer 2, and 5 μL ofwater for 4 hours at 37° C. The digested samples are then separated on a2% agarose gel in a field of 4 V/cm. The T allele remains undigested,yielding the full 410 base pair fragment, while the C allele is cut into162 and 248 bp fragments.

[0042] Outcome Measures

[0043] Discontinuations were classified as due to any event, and as dueto an adverse event. Severity of adverse events were obtained byclinician ratings that were standardised for drug exposure time anddosage. Plasma drug levels were obtained at day 28. Body weight wasdetermined at baseline and at each subsequent visit. Actual medicationtaken was determined by counting the number of tablets remaining at eachclinic visit. Dosing compliance was determined by as total number ofmedication doses taken divided by total number of capsules given.

[0044] Results

[0045] I. Genotypes Divided Two Ways (C/C Versus T/C and T/T Groups) AllSubjects

[0046] The frequencies of genotypes were:

[0047] Paroxetine C/C=41 patients (33.6%)

[0048] Paroxetine T carriers (T/C and T/T)=81 patients (66.4%)

[0049] Over the 8 week study, paroxetine C/C patients had:

[0050] Greater severity of adverse events due to study drug (p=.03)

[0051] Lower final daily dose (p=.08)

[0052] Lower dosing compliance (p=.06)

[0053] Lower plasma levels at day 28 (p=.056)

[0054] More subjects discontinuing early (p=.049), and more subjectsdiscontinuing early due to adverse events (46.3% for C/C genotype, 16%for other subjects; p=.001)

[0055] (p values above are from F tests comparing mean values, or fromCochran-Mantel-Haenszel statistics comparing proportions. These valuesindicate statistically significant (p<.05), or marginally statisticallysignificant (p<.10) differences).

[0056] The lower final daily dose, lower dosing compliance, and lowerplasma levels were likely due to more severe side effects in patientswith C/C genotype, resulting in decreased ability to take doses ofparoxetine that were well tolerated by other patients with the T/C andT/T genotypes.

[0057] Survival analyses for dropouts showed that patients with C/Cgenotype had significantly greater likelihood of dropping out of thestudy than did other subjects at every assessment point. Statisticsbelow are p values from Kaplan-Meier survival analyses. That is, at day7 the probability that the increased dropout rate of patients with theC/C genotype was due to random factors was only 0.001, or one inone-thousand. This indicates that these results are highly reliable. Allcauses Adverse events Day 7 .003 .001 Day 14 .005 .001 Day 21 .009 .001Day 28 .009 .001 Day 42 .014 .001 Day 49 .008 .001

[0058] Caucasian Subjects

[0059] There were no significant differences between the two genotypegroups in the frequency of ethnic minorities. However, because ofpossible effects of genetic background, data for Caucasians wereanalysed separately.

[0060] Paroxetine C/C=36 patients (33.0%)

[0061] Paroxetine T carriers (T/C and T/T)=73 patients (67.0%)

[0062] There were no significant differences between C/C and T/-groupsin age, gender, ethnicity, baseline body weight, cognition, or severityof depression at baseline.

[0063] Paroxetine C/C subjects had:

[0064] Greater severity of side effects due to study drug (p=.05 1)

[0065] More discontinuations due to any cause (C/C=63.9%; T/T andT/C=45.2%) p=.068

[0066] More discontinuations due to adverse events (C/C=47.2%; T/T andT/C=16.4%) p<.001

[0067] Survival Analyses showed C/C subjects had a significantly greaterprobability of discontinuation: All causes Adverse events Day 7 .006.001 Day 14 .010 .001 Day 21 .019 .002 Day 28 .019 .002 Day 42 .028 .004Day 49 .016 .001

[0068] I. Genotypes Divided Three Ways (C/C Versus T/C Versus T/T) AllSubjects

[0069] The data were also analysed with subjects divided into threegenotype groups.

[0070] 41 subjects with C/C genotype (33.6%)

[0071] 63 subjects with C/T genotype (51.6%)

[0072] 18 subjects with T/T genotype (14.8%)

[0073] 122 total

[0074] No significant differences were found between genotype groups inage, gender, ethnic origin, or body weight for either drug. Nosignificant differences were found among genotype groups in final dailydose achieved, dosing compliance, plasma drug concentrations at day 28.There were no differences in average daily dose at each visit, except atday 7, when C/C carriers took less medication than the other twogenotype groups. This was probably due to intolerance of the medicationin C/C carriers.

[0075] The probability of discontinuation due to an adverse event waslinearly related to increasing dosage of the C allele (C/C=3, C/T=2,T/T=1). That is, the greater the number of C alleles, the higher theprobability of discontinuation. All causes Adverse event Day 7: NS .016Day 14: .048 .010 Day 21: .047 .009 Day 28: .047 .009 Day 42: NS .020Day 49: .052 .009

[0076] Caucasian Subjects, 3-way Classification

[0077] 36 subjects with C/C genotype (33.0%)

[0078] 56 subjects with C/T genotype (56.0%)

[0079] 17 subjects with T/T genotype (15.6%)

[0080] There were no significant differences among the 3 genotype groups(C/C vs. T/C vs. T/T) in the frequency of ethnic minorities. However,because of possible effects of genetic background, data for Caucasianswere analysed separately.

[0081] Among Caucasian subjects, there were no significant differencesamong the genotype groups in age, gender, body weight, final daily dose,or overall dosing compliance.

[0082] At day 7, subjects with the C/C genotype took significantly lessparoxetine than subjects with C/T and T/T genotypes (p<.035).

[0083] Survival analyses did not show a difference among the 3 genotypegroups in discontinuations due to any cause. However, discontinuationsdue to adverse events showed: Day 7: 0.039 Day 14: 0.022 Day 21: 0.019Day 28: 0.019 Day 42: 0.051 Day 49: 0.020

[0084] Results for Mirtazapine

[0085] 122 additional patients with similar characteristics to thosetreated with paroxetine received mirtazapine treatment under the sameconditions. Initial treatment was with 15 mg mirtazapine (one activecapsule and one placebo capsule) given each evening. On day 14, doseswere increased to 30 mg once daily. At days 28 and 42, dose increases to45 mg of mirtazapine were allowed if the patient had a Clinical GlobalImpression (CGI) improvement score of greater than 2. All patients weregenotype for the 102 T/C polymorphism using the method described above.Results showed that mirtazapine-treated patients with the C/C genotypehad no greater probability of discontinuing treatment due to sideeffects than did other subjects, and no greater severity of side effectsthan others. These results are in marked contrast to those obtained withparoxetine treatment. Mirtazapine treated subjects also showedstatistically significant improvement in mood (decreased depression) asmeasured by the Hamilton Depression Rating Scale over the 8 weektreatment period. This result was not affected by the 102 T/Cpolymorphism.

[0086] Conclusion

[0087] These results illustrate the major effect of the 5-HT_(2A)receptor 102 T/C polymorphism on adverse events in patients treated withparoxetine. Subjects of the C/C genotype had a significantly higherprobability of discontinuation due to adverse events than did othersubjects at every evaluation point during the 8 week study. Subjects ofthe C/C genotype also took significantly less medication taken at day 7,and showed trends toward a lower final daily dose, and lower dosingcompliance. This suggests that the subjects with C/C found paroxetineunpleasant due to side effects. The side effects experienced by subjectswith the C/C genotype were more severe than those experienced by othersubjects. Typical side effects experienced by C/C carriers who droppedout of the study included dizziness, somnolence, insomnia, agitation,trouble concentrating, vomiting, nausea, and diarrhea.

[0088] The association between the 102 T/C polymorphism anddiscontinuations due to adverse events is present in both the fullsample as well as in the subsample of Caucasian subjects. This indicatesthat the result is not due to population stratification, meaning theresult is not due to including subjects of different ethnic backgroundsin the study. The result is robust regardless of whether the data areanalysed as C/C genotype vs. T/C and T/T or with three genotype levels(C/C., T/C., T/T).

[0089] The comparison study with mirtazapine showed that the 102 T/Cpolymorphism does not affect severity of side effects or dropouts due toside effects in depressed patients treated with this medication.Patients treated with mirtazapine, including those with C/C genotype,showed a statistically significant improvement in mood at the end of the8 week study. This indicates that therapy with mirtazapine is aneffective and safe alternative to SSRI treatment in patients who havethe C/C genotype.

1. A method for determining an increased risk for side effects ofselective serotonin reuptake inhibitor (SSRI) treatment in a subject,comprising genotyping the subject for the presence of the 102 C/C DNAsequence in the subject's 5-HT_(2A) receptor gene.
 2. The methodaccording to claim 1, wherein the subject suffers from depression.
 3. Amethod to improve a treatment of an SSRI responsive disorder in asubject, comprising genotyping the subject for the presence or absenceof the 102 C/C DNA sequence in the subject's 5-HT_(2A) receptor gene andadapting the further treatment differentially depending on the presenceor absence of the said sequence in the subject.
 4. The method accordingto claim 3, wherein the 102 C/C DNA sequence is found in the subject's5-HT_(2A) receptor gene and the subject is treated with a psychoactivepharmaceutical composition free of selective serotonin reuptakeinhibitors.
 5. The method according to claim 4, wherein the SSRIresponsive disorder is depression and the further treatment is adaptedby administering mirtazapine in an amount effective to treat depression.